Project Summary/Abstract Hyposmia, the reduced ability to smell, is very common in Parkinson?s disease (PD). Almost 90% of PD patients have hyposmia, which often develops about a decade before motor symptoms manifest. The pathology of PD is characterized by the presence of aggregated ?-synuclein in neurons across the brain; ?-Synuclein aggregation is believed to start in the olfactory brain regions, especially the olfactory bulb, and then spreads to other structures in the brain. The manifestation of the symptoms in PD is therefore believed to reflect the spreading of the pathology, explaining why olfactory deficits would manifest before other symptoms. In addition to ?-synuclein aggregation, there are other key processes that normally associate with PD ? neuronal death and neuroinflammation. There is, however, a fundamental gap in knowledge regarding the pathogenic mechanisms which cause hyposmia in PD. Thus, the objective of this multi-PI project is to establish how the progressive spreading of aggregated ?-synuclein from the olfactory bulb to other olfactory structures, and the associated neural cell death and neuroinflammation, trigger hyposmia. To this end, we will perform sophisticated measures of olfactory function (Wesson) in an experimental paradigm that we recently developed and which recreates spreading of ?-synuclein pathology across olfactory structures associated with olfactory deficits (Brundin). With this approach we will define the links between olfactory dysfunction and key underlying mechanisms of early PD, testing the hypothesis that ?- synuclein pathology progression from the olfactory bulb induces widespread neurodegeneration, protein aggregation, and neuroinflammation in the olfactory system, resulting in impaired olfaction. Specifically, we aim to demonstrate that ?-synuclein pathology affects odor information processing and to identify neuropathological underpinnings of these olfactory deficits. Further, we will test innovative approaches to modulate pathogenesis and to determine whether these interventions can improve olfactory function and/or stop the spreading of the pathology. These findings will provide fundamental information on the olfactory system and on how olfaction is impacted by specific neurodegenerative processes. We expect that our findings will eventually facilitate the development of therapeutic approaches to prevent the development of olfactory deficits associated with the spreading of ?-synuclein pathology across olfactory structures. Since these therapies should also prevent the spreading of ?- synuclein pathology to other brain regions, they have the potential to become disease-modifying interventions against PD.